The response of intrinsic brain cells to virus infection in the central nervous system (CNS) can contribute both to the pathogenesis of the virus infection as well as to the protection of the host. Our studies have utilized a mouse model of polytropic retrovirus infection to examine both the pathogenic and protective responses of the host in the CNS during virus infection. We have identified several host response proteins that are upregulated in the CNS following neurovirulent virus infection and may influence viral pathogenesis. In FY10, we primarily focused on one host protein in particular, neuropeptide Y (NPY). We found that NPY was produced by neurons at the late stages of virus infection in the CNS. Using knockout mice, we found that NPY plays a protective role during retrovirus infection and that mice deficient in NPY developed clinical disease at a much faster rate than wildtype mice. We further analyzed the mechanisms by which NPY influences retroviral pathogenesis in the CNS.